scholarly journals Inhibition of TrkB kinase activity impairs transdiaphragmatic pressure generation

2020 ◽  
Vol 128 (2) ◽  
pp. 338-344
Author(s):  
Miguel Pareja-Cajiao ◽  
Heather M. Gransee ◽  
Naomi A. Cole ◽  
Gary C. Sieck ◽  
Carlos B. Mantilla
Keyword(s):  
Neuromuscular Transmission ◽  
Kinase Activity ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Receptor Subtype ◽  
Transdiaphragmatic Pressure ◽  
Tracheal Occlusion ◽  
Motor Behaviors ◽  
Subtype B ◽  
Maximal Stimulation

Signaling via the tropomyosin-related kinase receptor subtype B (TrkB) regulates neuromuscular transmission, and inhibition of TrkB kinase activity by 1NMPP1 in TrkBF616A mice worsens neuromuscular transmission failure (NMTF). We hypothesized that acute inhibition of TrkB kinase activity will impair the ability of the diaphragm muscle to produce maximal transdiaphragmatic pressure (Pdi) without impacting the ability to generate forces associated with ventilation, consistent with the greater susceptibility to NMTF in motor units responsible for higher-force nonventilatory behaviors. Adult male and female TrkBF616A mice were injected with 1NMPP1 ( n = 8) or vehicle (DMSO; n = 8) 1 h before Pdi measurements during eupneic breathing, hypoxia/hypercapnia (10% O2/5% CO2), tracheal occlusion, spontaneous deep breaths (“sighs”) and during maximal activation elicited by bilateral phrenic nerve stimulation. In the vehicle-treated group, Pdi increased from ~10 cmH2O during eupnea and hypoxia/hypercapnia, to ~35 cmH2O during sighs and tracheal occlusion, and to ~65 cm H2O during maximal stimulation. There was no effect of acute 1NMPP1 treatment on Pdi generated during most behaviors, except during maximal stimulation (~30% reduction; P < 0.05). This reduction in maximal Pdi is generally similar to the worsening of NMTF previously reported with TrkB kinase inhibition in rodents. Accordingly, impaired TrkB signaling limits the range of motor behaviors accomplished by the diaphragm muscle and may contribute to neuromuscular dysfunction, primarily by impacting fatigable, higher force-generating motor units. NEW & NOTEWORTHY TrkB signaling plays an important role in maintaining neuromuscular function in the diaphragm muscle and may be necessary to accomplish the various motor behaviors ranging from ventilation to expulsive, behaviors requiring near-maximal forces. This study shows that inhibition of TrkB kinase activity impairs maximal pressure generation by the diaphragm muscle, but the ability to generate the lower pressures required for ventilatory behaviors is not impacted.

scholarly journals Diaphragm neuromuscular transmission failure in aged rats

2019 ◽  
Vol 122 (1) ◽  
pp. 93-104 ◽  
Author(s):  
Matthew J. Fogarty ◽  
Maria A. Gonzalez Porras ◽  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Nerve Stimulation ◽  
Phrenic Nerve ◽  
Neuromuscular Transmission ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Muscle Stimulation ◽  
Transmission Failure ◽  
Old Rats ◽  
Motor Neuron Loss ◽  
Fast Twitch

In aging Fischer 344 rats, phrenic motor neuron loss, neuromuscular junction abnormalities, and diaphragm muscle (DIAm) sarcopenia are present by 24 mo of age, with larger fast-twitch fatigue-intermediate (type FInt) and fast-twitch fatigable (type FF) motor units particularly vulnerable. We hypothesize that in old rats, DIAm neuromuscular transmission deficits are specific to type FInt and/or FF units. In phrenic nerve/DIAm preparations from rats at 6 and 24 mo of age, the phrenic nerve was supramaximally stimulated at 10, 40, or 75 Hz. Every 15 s, the DIAm was directly stimulated, and the difference in forces evoked by nerve and muscle stimulation was used to estimate neuromuscular transmission failure. Neuromuscular transmission failure in the DIAm was observed at each stimulation frequency. In the initial stimulus trains, the forces evoked by phrenic nerve stimulation at 40 and 75 Hz were significantly less than those evoked by direct muscle stimulation, and this difference was markedly greater in 24-mo-old rats. During repetitive nerve stimulation, neuromuscular transmission failure at 40 and 75 Hz worsened to a greater extent in 24-mo-old rats compared with younger animals. Because type IIx and/or IIb DIAm fibers (type FInt and/or FF motor units) display greater susceptibility to neuromuscular transmission failure at higher frequencies of stimulation, these data suggest that the age-related loss of larger phrenic motor neurons impacts nerve conduction to muscle at higher frequencies and may contribute to DIAm sarcopenia in old rats. NEW & NOTEWORTHY Diaphragm muscle (DIAm) sarcopenia, phrenic motor neuron loss, and perturbations of neuromuscular junctions (NMJs) are well described in aged rodents and selectively affect FInt and FF motor units. Less attention has been paid to the motor unit-specific aspects of nerve-muscle conduction. In old rats, increased neuromuscular transmission failure occurred at stimulation frequencies where FInt and FF motor units exhibit conduction failures, along with decreased apposition of pre- and postsynaptic domains of DIAm NMJs of these units.

scholarly journals Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period

2008 ◽  
Vol 104 (6) ◽  
pp. 1818-1827 ◽  
Author(s):  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Muscle Development ◽  
Respiratory Muscles ◽  
Motor Units ◽  
Perinatal Period ◽  
Diaphragm Muscle ◽  
Postnatal Maturation ◽  
Motor Behaviors ◽  
Phrenic Motoneurons ◽  
Phrenic Motoneuron ◽  
Key Aspects

At the time of birth, respiratory muscles must be activated to sustain ventilation. The perinatal development of respiratory motor units (comprising an individual motoneuron and the muscle fibers it innervates) shows remarkable features that enable mammals to transition from in utero conditions to the air environment in which the remainder of their life will occur. In addition, significant postnatal maturation is necessary to provide for the range of motor behaviors necessary during breathing, swallowing, and speech. As the main inspiratory muscle, the diaphragm muscle (and the phrenic motoneurons that innervate it) plays a key role in accomplishing these behaviors. Considerable diversity exists across diaphragm motor units, but the determinant factors for this diversity are unknown. In recent years, the mechanisms underlying the development of respiratory motor units have received great attention, and this knowledge may provide the opportunity to design appropriate interventions for the treatment of respiratory disease not only in the perinatal period but likely also in the adult.

TrkB Signaling Contributes to Transdiaphragmatic Pressure Generation in Aged Mice

2021 ◽  
Author(s):  
Miguel Pareja-Cajiao ◽  
Heather M. Gransee ◽  
Gary C. Sieck ◽  
Carlos B. Mantilla
Keyword(s):  
Old Age ◽  
Neuromuscular Transmission ◽  
Systemic Treatment ◽  
Diaphragm Muscle ◽  
Aging Effects ◽  
Phrenic Nerve Stimulation ◽  
Transdiaphragmatic Pressure ◽  
Neuromuscular Dysfunction ◽  
Breathing Room ◽  
Old Mice

Ventilatory deficits are common in old age and may result from neuromuscular dysfunction. Signaling via the tropomyosin-related kinase receptor B (TrkB) regulates neuromuscular transmission and in young mice is important for the generation of transdiaphragmatic pressure (Pdi). Loss of TrkB signaling worsened neuromuscular transmission failure and reduced maximal Pdi, and these effects are similar to those observed in old age. Administration of TrkB agonists such as 7,8-dihydroxyflavone (7,8-DHF) improves neuromuscular transmission in young and old mice (18 months; 75% survival). We hypothesized that TrkB signaling contributes to Pdi generation in old mice, particularly during maximal force behaviors. Old male and female TrkBF616A mice, with a mutation that induces 1NMPP1-mediated TrkB kinase inhibition, were randomly assigned to systemic treatment with vehicle, 7,8-DHF, or 1NMPP1 one hour prior to experiments. Pdi was measured during eupneic breathing (room air), hypoxia-hypercapnia (10% O2/5% CO2), tracheal occlusion, spontaneous deep breaths ("sighs"), and bilateral phrenic nerve stimulation (Pdimax). There were no differences in the Pdi amplitude across treatments during ventilatory behaviors (eupnea, hypoxia-hypercapnia, occlusion or sigh). As expected, Pdi increased from eupnea and hypoxia-hypercapnia (~7 cm H2O) to occlusion and sighs (~25 cm H2O), with no differences across treatments. Pdimax was ~50 cm H2O in the vehicle and 7,8-DHF groups and ~40 cm H2O in the 1NMPP1 group (F8,74 = 2; p = 0.02). Our results indicate that TrkB signaling is necessary for generating maximal forces by the diaphragm muscle in old mice, and are consistent with aging effects of TrkB signaling on neuromuscular transmission.

Diaphragmatic failure during loaded breathing: role of neuromuscular transmission

1993 ◽  
Vol 74 (4) ◽  
pp. 1679-1683 ◽  
Author(s):  
A. R. Bazzy ◽  
D. F. Donnelly
Keyword(s):  
Phrenic Nerve ◽  
Neuromuscular Transmission ◽  
Diaphragm Muscle ◽  
Plateau Phase ◽  
Nerve Activity ◽  
Transdiaphragmatic Pressure ◽  
M Wave ◽  
Arterial Pco2 ◽  
Loaded Breathing

To determine whether central or peripheral mechanisms are responsible for diaphragmatic failure during loaded breathing, phrenic nerve activity (iENG), diaphragm muscle electromyogram (iEMG), and transdiaphragmatic pressure (Pdi) were measured in unanesthetized chronically instrumented sheep during inspiratory flow-resistive (IFR) loaded breathing. After placement of the IFR load, Pdi increased initially and remained relatively stable for 10–30 min [Pdi = 69.9 +/- 6.3 (SE) cmH2O, n = 6]; arterial PCO2 also increased from baseline (35.8 +/- 0.9 Torr) to 55.1 +/- 4.7 Torr. During IFR loading, iEMG and iENG also increased from baseline, but during the plateau phase of Pdi, iENG continued to increase at the same time while iEMG was stable, and the M wave, evoked by phrenic nerve stimulation, decreased during this period. After the plateau phase, Pdi decreased and arterial PCO2 increased, at which point the study was terminated (at 82.1 +/- 20.6 min). The observation that iENG increased while Pdi and iEMG were stable demonstrates a reduced efficiency of neuromuscular transmission and suggests that the neuromuscular junction is an important site of diaphragmatic failure in unanesthetized sheep during IFR loaded breathing.

scholarly journals Diaphragm electromyographic activity following unilateral midcervical contusion injury in rats

2017 ◽  
Vol 117 (2) ◽  
pp. 545-555 ◽  
Author(s):  
Sabhya Rana ◽  
Gary C. Sieck ◽  
Carlos B. Mantilla
Keyword(s):  
Motor Units ◽  
Diaphragm Muscle ◽  
Emg Activity ◽  
High Threshold ◽  
Perineuronal Net ◽  
Neural Drive ◽  
Motor Behaviors ◽  
Neuromotor Control ◽  
Phrenic Motoneurons ◽  
Contusion Injury

Contusion-type injuries to the spinal cord are characterized by tissue loss and disruption of spinal pathways. Midcervical spinal cord injuries impair the function of respiratory muscles and may contribute to significant respiratory complications. This study systematically assessed the impact of a 100-kDy unilateral C4 contusion injury on diaphragm muscle activity across a range of motor behaviors in rats. Chronic diaphragm electromyography (EMG) was recorded before injury and at 1 and 7 days postinjury (DPI). Histological analyses assessed the extent of perineuronal net formation, white-matter sparing, and phrenic motoneuron loss. At 7 DPI, ∼45% of phrenic motoneurons were lost ipsilaterally. Relative diaphragm root mean square (RMS) EMG activity increased bilaterally across a range of motor behaviors by 7 DPI. The increase in diaphragm RMS EMG activity was associated with an increase in neural drive (RMS value at 75 ms after the onset of diaphragm activity) and was more pronounced during higher force, nonventilatory motor behaviors. Animals in the contusion group displayed a transient decrease in respiratory rate and an increase in burst duration at 1 DPI. By 7 days, following midcervical contusion, there was significant perineuronal net formation and white-matter loss that spanned 1 mm around the injury epicenter. Taken together, these findings are consistent with increased recruitment of remaining motor units, including more fatigable, high-threshold motor units, during higher force, nonventilatory behaviors. Changes in diaphragm EMG activity following midcervical contusion injury reflect complex adaptations in neuromotor control that may increase the risk of motor-unit fatigue and compromise the ability to sustain higher force diaphragm efforts. NEW & NOTEWORTHY The present study shows that unilateral contusion injury at C4 results in substantial loss of phrenic motoneurons but increased diaphragm muscle activity across a range of ventilatory and higher force, nonventilatory behaviors. Measures of neural drive indicate increased descending input to phrenic motoneurons that was more pronounced during higher force, nonventilatory behaviors. These findings reveal novel, complex adaptations in neuromotor control following injury, suggestive of increased recruitment of more fatigable, high-threshold motor units.

scholarly journals Recruitment of rat diaphragm motor units across motor behaviors with different levels of diaphragm activation

2014 ◽  
Vol 117 (11) ◽  
pp. 1308-1316 ◽  
Author(s):  
Yasin B. Seven ◽  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Motor Unit ◽  
Motor Neurons ◽  
Motor Units ◽  
Motor Unit Recruitment ◽  
Diaphragm Muscle ◽  
Emg Activity ◽  
Motor Behaviors ◽  
Airway Occlusion ◽  
Recruitment Order ◽  
Central Drive

Phrenic motor neurons are recruited across a range of motor behaviors to generate varying levels of diaphragm muscle (DIAm) force. We hypothesized that DIAm motor units are recruited in a fixed order across a range of motor behaviors of varying force levels, consistent with the Henneman Size Principle. Single motor unit action potentials and compound DIAm EMG activities were recorded in anesthetized, neurally intact rats across different motor behaviors, i.e., eupnea, hypoxia-hypercapnia (10% O2 and 5% CO2), deep breaths, sustained airway occlusion, and sneezing. Central drive [estimated by root-mean-squared (RMS) EMG value 75 ms after the onset of EMG activity (RMS75)], recruitment delay, and onset discharge frequencies were similar during eupnea and hypoxia-hypercapnia. Compared with eupnea, central drive increased (∼25%) during deep breaths, and motor units were recruited ∼12 ms earlier ( P < 0.01). During airway occlusion, central drive was ∼3 times greater, motor units were recruited ∼30 ms earlier ( P < 0.01), and motor unit onset discharge frequencies were significantly higher ( P < 0.01). Recruitment order of motor unit pairs observed during eupnea was maintained for 98%, 87%, and 84% of the same pairs recorded during hypoxia-hypercapnia, deep breaths, and airway occlusion, respectively. Reversals in motor unit recruitment order were observed primarily if motor unit pairs were recruited <20 ms apart. These results are consistent with DIAm motor unit recruitment order being determined primarily by the intrinsic size-dependent electrophysiological properties of phrenic motor neurons.

scholarly journals TrkB kinase activity maintains synaptic function and structural integrity at adult neuromuscular junctions

2014 ◽  
Vol 117 (8) ◽  
pp. 910-920 ◽  
Author(s):  
Carlos B. Mantilla ◽  
Jessica M. Stowe ◽  
Dylan C. Sieck ◽  
Leonid G. Ermilov ◽  
Sarah M. Greising ◽  
...  
Keyword(s):  
Neuromuscular Transmission ◽  
Kinase Activity ◽  
Structural Integrity ◽  
Neuromuscular Junctions ◽  
Morphological Changes ◽  
Synaptic Function ◽  
Diaphragm Muscle ◽  
Presynaptic Terminals ◽  
Reversible Inactivation ◽  
Motor End Plates

Activation of the tropomyosin-related kinase receptor B (TrkB) by brain-derived neurotrophic factor acutely regulates synaptic transmission at adult neuromuscular junctions (NMJs). The role of TrkB kinase activity in the maintenance of NMJ function and structure at diaphragm muscle NMJs was explored using a chemical-genetic approach that permits reversible inactivation of TrkB kinase activity in TrkB F616A mice by 1NMPP1. Inhibiting TrkB kinase activity for 7 days resulted in significant, yet reversible, impairments in neuromuscular transmission at diaphragm NMJs. Neuromuscular transmission failure following 2 min of repetitive phrenic nerve stimulation increased from 42% in control to 59% in 1NMPP1-treated TrkB F616A mice ( P = 0.010). Recovery of TrkB kinase activity following withdrawal of 1NMPP1 treatment improved neuromuscular transmission ( P = 0.006). Electrophysiological measurements at individual diaphragm NMJs documented lack of differences in quantal content in control and 1NMPP1-treated mice ( P = 0.845). Morphological changes at diaphragm NMJs were modest following inhibition and recovery of TrkB kinase activity. Three-dimensional reconstructions of diaphragm NMJs revealed no differences in volume at motor end plates (labeled by α-bungarotoxin; P = 0.982) or presynaptic terminals (labeled by synaptophysin; P = 0.515). Inhibition of TrkB kinase activity by 1NMPP1 resulted in more compact NMJs, with increased apposition of presynaptic terminals and motor end plates ( P = 0.017) and reduced fragmentation of motor end plates ( P = 0.005). Recovery of TrkB kinase activity following withdrawal of 1NMPP1 treatment resulted in postsynaptic remodeling likely reflecting increased gutter depth ( P = 0.007), without significant presynaptic changes. These results support an essential role for TrkB kinase activity in maintaining synaptic function and structural integrity at NMJs in the adult mouse diaphragm muscle.

scholarly journals Functional impact of diaphragm muscle sarcopenia in both male and female mice

2015 ◽  
Vol 309 (1) ◽  
pp. L46-L52 ◽  
Author(s):  
Sarah M. Greising ◽  
Carlos B. Mantilla ◽  
Juan S. Medina-Martínez ◽  
Jessica M. Stowe ◽  
Gary C. Sieck
Keyword(s):  
Functional Limitations ◽  
Diaphragm Muscle ◽  
Specific Force ◽  
Transdiaphragmatic Pressure ◽  
Male And Female ◽  
Female Mice ◽  
Motor Behaviors ◽  
Age Related

To perform a range of ventilatory and nonventilatory behaviors, the diaphragm muscle (DIAm) must be able to generate sufficient forces throughout the lifespan. We hypothesized that sarcopenia impacts DIAm force generation and thus limits performance of expulsive, higher force, nonventilatory behaviors. Male and female mice ( n = 79) at 6 and 24 mo of age (100 vs. 70–75% survival, respectively) were used to examine transdiaphragmatic pressure (Pdi) generation across motor behaviors in vivo and in vitro DIAm specific force. We found a significant effect of age on maximum Pdi (20–41% decline during tracheal occlusion and bilateral phrenic nerve stimulation), maximum DIAm specific force (30% decline), and DIAm fatigue resistance (15% increase). There were no differences between sexes in these age effects on DIAm performance. These results support our hypothesis that sarcopenia primarily impacts higher force, nonventilatory motor behaviors of the DIAm. Such functional limitations may have negative implications in the ability of the DIAm to generate forces needed for airway clearance in old age and thereby contribute to age-related respiratory complications.

scholarly journals Motor unit number and transmission stability in octogenarian world class athletes: Can age-related deficits be outrun?

2016 ◽  
Vol 121 (4) ◽  
pp. 1013-1020 ◽  
Author(s):  
Geoffrey A. Power ◽  
Matti D. Allen ◽  
Kevin J. Gilmore ◽  
Daniel W. Stashuk ◽  
Timothy J. Doherty ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Neuromuscular Transmission ◽  
Compound Muscle Action Potential ◽  
Motor Units ◽  
Maximum Voluntary Isometric Contraction ◽  
High Performing ◽  
Highly Active ◽  
Age Related ◽  
World Class ◽  
World Champion

Our group has shown a greater number of functioning motor units (MU) in a cohort of highly active older (∼65 yr) masters runners relative to age-matched controls. Because of the precipitous loss in the number of functioning MUs in the eighth and ninth decades of life it is unknown whether older world class octogenarian masters athletes (MA) would also have greater numbers of functioning MUs compared with age-matched controls. We measured MU numbers and neuromuscular transmission stability in the tibialis anterior of world champion MAs (∼80 yr) and compared the values with healthy age-matched controls (∼80 yr). Decomposition-enhanced spike-triggered averaging was used to collect surface and intramuscular electromyography signals during dorsiflexion at ∼25% of maximum voluntary isometric contraction. Near fiber (NF) MU potential analysis was used to assess neuromuscular transmission stability. For the MAs compared with age-matched controls, the amount of excitable muscle mass (compound muscle action potential) was 14% greater ( P < 0.05), there was a trend ( P = 0.07) toward a 27% smaller surface-detected MU potential representative of less collateral reinnervation, and 28% more functioning MUs ( P < 0.05). Additionally, the MAs had greater MU neuromuscular stability than the controls, as indicated by lower NF jitter and jiggle values ( P < 0.05). These results demonstrate that high-performing octogenarians better maintain neuromuscular stability of the MU and mitigate the loss of MUs associated with aging well into the later decades of life during which time the loss of muscle mass and strength becomes functionally relevant. Future studies may identify the concomitant roles genetics and exercise play in neuroprotection.

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